General (including evidence of efficacy)

Background

Activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in development and progression of heart failure (HF). Angiotensin II, one of the most potent neurohormones in this system, is known to cause vasoconstriction, sodium retention, cardiac hypertrophy, cell death, endothelial dysfunction and other detrimental cardiovascular effects. Most of these actions are mediated through angiotensin II type 1 (AT1) receptor. Angiotensin receptor blockers (ARBs) selectively block the binding of angiotensin II to the AT1 receptor.

Evidence for ARBs as Alternatives to ACE Inhibitors in Patients with Chronic HF

With the proven efficacy of ACE inhibitors in HF with depressed systolic function, a number of trials evaluated the efficacy of ARBs in comparison to ACE inhibitors. The Evaluation of Losartan In The Elderly I (ELITE I) trial in elderly patients with symptomatic heart failure and LV systolic dysfunction demonstrated no significant difference in primary endpoint of a persistent increase of > 0.3 mg/dL in serum creatinine between the losartan and captopril groups, but did suggest better long-term outcomes with the ARB.

A second larger trial, the Evaluation of Losartan In The Elderly II (ELITE II) showed no significance difference in all-cause mortality with treatment with captopril versus losartan in patients with HF. Indeed, ACE inhibitors appeared to be marginally superior to ARBs (hazard ratio 1.13, 95% CI 0.95-1.35, p=0.16). Though this finding may be interpreted as lending support to the possibility that the bradykinin effects of ACE inhibitors may confer a practical benefit in patients with heart failure, it also has been suggested that the dose of losartan used in the ELITE trials (50 mg daily) may not fully block AT1 receptors.

Based on the ELITE II trial, ACE inhibitors continued to be recommended as first-line agents of choice for patients with HF and depressed ejection fraction, but if patients were unable to tolerate ACE inhibitors for adverse events such as cough or angioedema, ARBs were offered as useful alternative agents to block the RAAS. Further support for ARBs as an alternative strategy in patients with HF intolerant to ACE inhibitors was provided by results of the Valsartan in Heart failure trial (Val-HeFT) in the small subgroup of patients (7%) not on an ACE inhibitors at baseline, which showed a 33% reduction in mortality and a 49% decrease in mortality and morbidity with valsartan.

The definitive answer to whether ARBs are an effective alternative in patients with systolic HF who are intolerant to ACE inhibitors was provided by the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial. Patients with symptomatic HF with depressed ejection and history of intolerance to ACE inhibitors were randomized to either the ARB, candesartan or to placebo. Candesartan was associated with a significant 23% reduction in the primary composite outcome of cardiovascular mortality or HF hospitalization (hazard ratio 0.77, 95% CI 0.67-0.89; p= 0.0004).

Thus, the results of the CHARM-alternative study, along with subgroup analysis in the Val-HeFT trial of 7% of patients who were not on ACE inhibitors, have shown that ARBs (specifically candesartan and valsartan) confer significant benefit on mortality and morbidity in patients with HF who are intolerant of ACE inhibitors and therefore constitute a good alternative strategy in these patients.

Evidence for ARBs in Addition to ACE Inhibitors in Patients with Chronic HF

Two large recent clinical trials, the Valsartan Heart failure trial (Val-HeFT) and the CHARM-Added trial, have since evaluated the benefit on morbidity and mortality of adding ARBs in patients with HF already on ACE inhibitors. In Val-HeFT, valsartan started at a dose of 40 mg twice daily, titrated up to 80 mg twice daily and then to 160 mg twice daily on background therapy with ACE inhibitors (93%) and beta blockers (35%) in patients with symptomatic systolic HF, reduced the combined mortality and morbidity end point by 13.2%.

This was primarily due to 24% reduction in the rate of hospitalizations for HF, rather than mortality. The CHARM-Added trial also demonstrated that in patients with symptomatic systolic HF already on treatment with an ACE inhibitor, beta-blockers (55%), candesartan reduced cardiovascular death or heart failure hospitalization (unadjusted HR 0.85; 95% CI 0.75-0.96; p= 0.01).

Evidence for ARBs in Patients with Chronic HF and Preserved Ejection Fraction (HF-PEF)

ARBs as well as ACE inhibitors have been shown to slow the progression, or induce regression, of left ventricular hypertrophy through their effects on blood pressure and on the myocardium; but failed to demonstrate any mortality benefit in HF-PEF. The CHARM-Preserved trial assessed whether candesartan would have a beneficial effect on the composite outcome of cardiovascular mortality or HF hospitalization in patients with HF-PEF; and showed no significant difference in the primary endpoint of cardiovascular death or HF hospitalization (HR 0.89, 95% CI 0.77-1.03; p=0.118). Similarly, in the I-PRESERVE trial, treatment with irbesartan did not show any significant benefit in all-cause mortality or CV hospitalizations in patients with HF-PEF.

Evidence for ARBs in High Risk Patients Post Myocardial Infarction

ACE inhibitors have consistently been beneficial in improving morbidity and mortality in high-risk patients post myocardial infarction. ARBs have been evaluated for benefit in high-risk patients post myocardial infarction, both as an alternative to ACE inhibitors and when added onto ACE inhibitor therapy. In the Optimal Trial In Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL), losartan (50 mg/day), when compared to the ACE inhibitor, captopril (150 mg/day), in high risk patients post acute myocardial infarction showed a strong but nonsignificant trend in favor of captopril over losartan in the primary endpoint of all-cause mortality (RR 1.13, 95% CI 0•99–1•28, p=0.07).

A prespecified endpoint of CV mortality reached significance in favor of captopril (p=0.03) and first HF hospitalization trended in favor captopril (RR for losartan: captopril 1.16, 95% CI 0.98, 1.37, p=0.07). The relatively low dose and slow uptitration course of losartan in this study may have contributed to these results. Valsartan in Acute Myocardial Infarction trial (VALIANT) compared effects of valsartan, captopril or both in a high risk patient population with clinical or radiological evidence of HF and/or evidence of left ventricular systolic dysfunction following acute myocardial infarction, and demonstrated valsartan was comparable to captopril in terms of the overall mortality as well as the composite end point of fatal and non-fatal cardiovascular outcomes.

Whereas patients receiving combined therapy experienced the most drug related adverse events, adverse events were less common for monotherapy, with hypotension and renal dysfunction being more common in the valsartan group and cough, skin rash and taste disturbance more common in the captopril group.

Evidence for ARBs in Asymptomatic Left Ventricular Systolic Dysfunction

ACE inhibitors are recommended for all patients with asymptomatic left ventricular systolic dysfunction to reduce progression to HF. However, at present there are no data to support the combination of ACE inhibitors and ARBs in patients with asymptomatic left ventricular systolic dysfunction. Even though there are no data to confirm equivalence of ARBs to ACE inhibitors in this patient population, data from the post MI patients and patients with symptomatic heart failure studies in the VALIANT and CHARM trials allow us to extrapolate that the ARBs, valsartan and candesartan, should be used in patients with asymptomatic left ventricular systolic dysfunction who are intolerant to ACE inhibitors.

Differences between drugs within the class

Are All ARBs the Same?

Although all ARBs as a group block the AT1 receptor, they differ in pharmacokinetics, including differences in binding characteristics. AT1 receptor antagonism has been classified as surmountable and insurmountable based on the ability to shift the angiotensin-II concentration-response curve to the right. Surmountable antagonism implies that the blockade by the antagonist can be overcome with increasing concentrations of agonist or angiotensin II, whereas with insurmountable antagonism, the blockade by the antagonist cannot be overcome with increasing concentrations of angiotensin II.

Thus, insurmountable antagonism is associated with a reduction in maximal angiotensin II response whereas surmountable antagonism is not. With the use of ARBs, plasma angiotensin II concentrations increase as a result of interrupting the negative feedback in the RAAS. This provides a theoretical rationale for more clinical benefit with use of an insurmountable AT1 receptor blocker antagonist. An insurmountable, long-acting AT1 receptor antagonist that displays tight binding characteristics is not likely to be overcome by the higher levels of circulating angiotensin II. Valsartan, irbesartan, candesartan and an active metabolite of losartan, are insurmountable AT1 receptor antagonists, while losartan is a surmountable antagonist.

Whether this is a contributing factor to the better results seen in clinical trials using valsartan or candesartan compared to losartan in patients with HF is, however, not clear. Results of better clinical efficacy with a higher dose of losartan as addressed in the subsequent section underline the importance of the appropriate dose for these agents, which may explain some of the differences in outcomes in clinical trials with certain agents.

Is it the Medication or is it the Dose?

Another important factor that makes the interpretation of differences in benefits noted between different ARBs difficult is the issue of appropriate dosing. Choosing the appropriate dose of a therapeutic agent is perhaps equally as important as choosing the correct therapeutic agent. For example, the dosing strategy of 50 mg/day of losartan vs. 150 mg/day of captopril favored captopril in the OPTIMAAL trial, and favored the use of captopril over losartan in patients with moderate to severe heart failure in the ELITE II trial.

The dosing issue was addressed in the HEAAL (Heart failure Endpoint evaluation of Angiotensin I Antagonists Losartan) trial which compared the effects of high-dose (150 mg daily) versus low-dose (50 mg daily) losartan on clinical outcomes in 3,846 patients with NYHA Class II-IV heart failure, LVEF 40% or less, and intolerance to angiotensin-converting-enzyme inhibitors. In those patients, Losartan 150 mg daily reduced the rate of death or admission for heart failure compared with losartan 50 mg daily (HR 0·90, 95% CI 0·82-0·99; p=0·027). Renal impairment, hypotension and hyperkalemia were slightly more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group.

These findings underline the value of up-titrating ARB doses to confer clinical benefit, and that the dose indeed is important. It is clear from HEAAL that should losartan be used to treat a patient with heart failure, the target dose should be 150 mg , but with caution for hyperkalemia, renal dysfunction or hypotension compared with a dose of 50 mg daily. Similarly, in clinical trials of two high-risk patient populations with hypertensive left ventricular hypertrophy and with diabetic nephropathy, higher doses of losartan up to 100 mg/day were associated with a significant reduction in the incidence of HF, raising the question of whether higher doses of losartan could have been more effective in reducing cardiovascular outcomes in OPTIMAAL and ELITE II.

VALIANT tested a higher dose of valsartan (160 mg twice daily), a dose that is higher than its usual indicated dose in hypertension (160 mg daily). This may have contributed to its equivalent benefit compared to captopril in that trial. The fact that there were greater reductions in blood pressure and more frequent hypotension-related adverse effects with valsartan in VALIANT compared with losartan in OPTIMAAL relative to the captopril comparator, also supports this view.

Given that valsartan was as effective as captopril in reducing death and other adverse cardiovascular events, the question raised by the VALIANT trial is whether high-risk patients should receive an ACE inhibitor or an ARB following acute myocardial infarction. A number of factors may weigh in on the choice between these two agents including the cumulative clinical experience and tolerability.

In contrast to the HF trials, wherein combined therapy with ACE inhibitors and ARBs was shown to be beneficial on cardiovascular morbidity (Val-HeFT) and mortality (CHARM), VALIANT trial showed that combined therapy resulted in an increase in adverse events without improving overall survival. A number of reasons have been offered for the discrepant results in the combination arm of VALIANT compared to those of the CHARM and Val-HeFT trials.

First, the natural history of acute myocardial infarction (VALIANT) is different from chronic HF. HF hospitalizations tend to be a significant event for chronic HF patients, while myocardial infarction patients tend to have recurrent infarctions and early cardiac death. The main effects of drugs that block the RAAS may be a reduction in HF events, as was the main effect shown with ARBs in the CHARM and Val-HeFT studies. Thus it may be easier to show a benefit of combination therapy with an ACE inhibitor and an ARB in HF than in myocardial infarction patients. In addition, in the CHARM and Val-HeFT studies, the ARB was added on to treatment in patients who had already been taking ACE inhibitors long term, whereas in VALIANT both drugs were started concurrently.

The RAAS escape is seen in patients on chronic ACE inhibition therapy where significant angiotensin II is formed by non-ACE pathways. In that situation, a beneficial effect may be more likely to be seen if an ARB is added. But in the post-myocardial infarction state, if both the ACE inhibitors and ARB are started together, the escape mechanism may not be present leading to less benefit from an ARB.

Furthermore, VALIANT is the only trial among the ARB trials in which the dose of the ACE inhibitor was titrated up to a maximum target. This resulted in a higher dose of ACE inhibitors in VALIANT (mean captopril dose 117 mg) than in CHARM (mean captopril dose of about 80 mg). This may have decreased the chances to observe the beneficial effect of addition of an ARB in VALIANT.

Also, the VALIANT trial employed a high dose of valsartan (160 mg twice daily) in the monotherapy arm, but this dose was halved in the combination arm, raising the possibility that the dose may not have been high enough to show a benefit when added to full-dose ACE inhibition. This was in contrast to the CHARM and Val-HeFT, which used high target ARB doses in all patients. Taken together, data do not support the routine addition of ARBs to standard therapy with target doses of ACE inhibitors and beta blockers in high-risk patients post acute myocardial infarction.

Administration

Initiation and maintenance

When used, angiotensin receptor antagonists should be initiated with the starting doses (see Table I and Table II).

Table I.

ARBs Commonly Used for the Treatment of Patients with HF

Drug

Initial Daily Dose(s)

Maximum Doses(s)

Mean Doses Achieved in Clinical Trials

Candesartan

4-8 mg once

32 mg once

24 mg/day

Losartan

25-50 mg once

50-150 mg once

129 mg/day

Valsartan

20-40 mg twice

160 mg twice

254 mg/day

Table II.

ARBs Approved for Indications Other than HF

Drug

Initial Daily Dose

Maximum Daily Dose

Approved fo r the Indication of

Eprosartan

600 mg

800 mg

Hypertension

Irbesartan

150 mg

300 mg

Hypertension and Diabetic Nephropathy

Olmesartan

20 mg

40 mg

Hypertension

Telmisartan

40 mg

80 mg

Hypertension and Primary Prevention of CVD in High Risk Patients

Blood pressure (including postural blood pressure changes), renal function, and potassium should be reassessed within 1-2 weeks after initiation and followed closely after changes in dose. Patients with systolic blood pressure below 80 mm Hg, low serum sodium, diabetes mellitus, and impaired renal function merit particular surveillance during therapy with ARBs. Titration is generally achieved by doubling doses. For stable patients, it is reasonable to add therapy with beta-blocking agents before full target doses of either ACEIs or ARBs are reached.

The risks of treatment with ARBs are those attributed to suppression of angiotensin stimulation. These risks of hypotension, renal dysfunction and hyperkalemia are greater when combined with another inhibitor of this axis, such as ACEIs or aldosterone antagonists.

Pharmacologic action

Rationale for Use of Angiotensin Receptor Blockers in Heart Failure

ACE inhibitors block the action of ACE, the converting enzyme of angiotensin I to angiotensin II, and reduce angiotensin II (Figure 1). However, ACE inhibitor treatment does not lead to complete suppression of angiotensin II levels, which gradually increase despite chronic high-dose ACE inhibitor therapy (Ace inhibitor escape phenomenon). Competitive inhibition of ACE results in increases in both renin and angiotensin I, which then tend to overcome the blockade of this enzyme. In addition, angiotensin II production also occurs through non-ACE pathways (such as chymase, kallikrein, cathepsin G and tonin), that convert angiotensin I to angiotensin II (non Ace pathways (Figure 1). These considerations provided the rationale for the development of ARBs that offer more complete protection against angiotensin II by directly blocking the AT1 receptor.

Figure 1.

Activation of the Renin Angiotensin System and AT1 and AT2 receptors:
Angiotensinogen is converted to angiotensin I by renin. Angiotensin I can be converted to angiotensin II through angiotensin converting enzyme (ACE) and non-ACE dependent pathways. Angiotensin II exerts its biological effects binding to a type I (AT1) and type II (AT2) angiotensin receptor. Only 30-40% of angiotensin I to angiotensin II conversion occurs via the ACE pathway. Up to 60-70% of angiotensin I to angiotensin II conversion occurs via the non-ACE pathways including chymase, tonin, cathepsin and kallikrein.

Beneficial effects of ACE inhibitors are also thought in part to be due to their augmentation of the effects of bradykinin. ACE inhibitors block the breakdown of bradykinin (Figure 1), which has direct and indirect vasodilator activity through the release of nitric oxide and prostaglandin, as well as having antimitotic and antithrombotic actions that could be of benefit in heart failure. On the other hand, bradykinin is also likely responsible for the adverse reaction of cough with the use of ACE inhibitors. Compared to ACE inhibitors, ARBs do not increase bradykinin and do not cause cough. These differences in neurohormonal modulation and adverse effects between ACE inhibitors and ARBs suggest that the benefits and risks of these agents may differ in patients with HF.

Indications and contraindications

Clinical Benefit Summary and Current Guidelines

ARBs have been studied in large scale clinical trials and determined to be beneficial:

In HF patients with reduced LVEF, who are ACE-(angiotensin-converting enzyme) inhibitor intolerant.

As an add-on therapy for HF patients with reduced LVEF who are already being treated with Ace-inhibitors and beta-blockers.

In post myocardial infarction patients who have left ventricular systolic dysfunction and who are Ace-inhibitor intolerant.

Indications

Current ACCF/ AHA Guidelines for Diagnosis and Management of Heart Failure recommends the following treatment strategies with ARBs in patients with HF:

In Patients at High Risk for Developing Heart Failure (Stage A):

ARBs can be useful to prevent HF in patients at high risk for developing HF who have a history of atherosclerotic vascular disease, diabetes mellitus or hypertension with associated cardiovascular risk factors (Class IIa, Level of Evidence C).

In Patients With Cardiac Structural Abnormalities or Remodeling Who Have Not Developed Heart Failure Symptoms (Stage B):

An ARB should be administered to post-MI patients without HF who are intolerant of ACEIs and have a low LVEF. (Class I, Level of Evidence: B).

Ace-inhibitors or ARBs can be beneficial in patients with hypertension and LVH and no symptoms of HF. (Class IIa, Level of Evidence: B).

ARBs can be beneficial in patients with low EF and no symptoms of HF who are intolerant of ACEIs (Class IIa, Level of Evidence: C).

In Patients With Current or Prior Symptoms of HF (Stage C):

Angiotensin II receptor blockers (see Table I) are recommended in patients with current or prior symptoms of HF and reduced LVEF who are ACEI-intolerant (Class I, Level of Evidence: A).

Angiotensin II receptor blockers are reasonable to use as alternatives to ACEIs as first-line therapy for patients with mild to moderate HF and reduced LVEF, especially for patients already taking ARBs for other indications (Class IIa, Level of Evidence: A).

The addition of an ARB may be considered in persistently symptomatic patients with reduced LVEF who are already being treated with conventional therapy of Ace inhibitors and beta-blockers. (Class IIb, Level of Evidence: B).

Routine combined use of an ACEI, ARB and aldosterone antagonist is not recommended for patients with current or prior symptoms of HF and reduced LVEF. (Class III, Level of Evidence: C).

Intolerance to Ace inhibitors due to hypotension, renal insufficiency and hyperkalemia. ARBs are as likely to produce hypotension, worsening renal function and hyperkalemia. Angioedema is much less frequent with ARBs, but there are cases of patients who developed angioedema to ACE inhibitors and later to ARBs.

Routine combined use of an ACEI, ARB and aldosterone antagonist is not recommended in HF patients.

Undesirable effects

The risks of treatment with ARBs are those attributed to suppression of angiotensin stimulation. These risks, which include hypotension, renal dysfunction and hyperkalemia, are greater in diabetic patients, patients with lower baseline renal function, elderly patients or when combined with another inhibitor of this axis, such as ACE inhibitors or aldosterone antagonists.

Common listed other side effects include headache, drowsiness, diarrhea, abnormal taste sensation and rash. Compared to ACE inhibitors, cough occurs less often with ARBs due to no significant increase in bradykinin levels. Liver failure, allergic reactions, leucopenia, angioedema are rare but have been reported with ARB use. ARBs should not be prescribed during pregnancy (Class C/D medication) due to birth defects. Like other antihypertensives, ARBs have also been associated with sexual dysfunction.

Alternative approaches

At present, based on a much larger experience and efficacy of ACE inhibitors compared to ARBs, ACE inhibitors continue to be first-line therapy for HF patients with reduced EF and post myocardial infarction patients. In patients intolerant of ACE inhibitors, ARBs at target doses utilized in clinical trials, should be used as alternative agents. The routine addition of ARBs to ACE inhibitor therapy is not recommended in high-risk patients post-myocardial infarction. However, in chronic HF, the addition of ARBs may be considered in patients who continue to be significantly symptomatic with heart failure or have uncontrolled hypertension, despite target doses of ACE inhibitors and beta blockers. Even in this highly symptomatic patient population, it is at present unclear whether an aldosterone inhibitor or an ARB should be added first.